MS Abstracts 04d-2g6

Classical knowledge distinguishes between inflammatory and non-inflammatory diseases of the Brain.

Either the Immune System acts on the CNS and initiates a damage cascade, as in Autoimmune (e.g. Multiple Sclerosis) and infectious conditions.

Or, the primary insult is not inflammation but Ischemia or degeneration, as in Stroke and Alzheimer's Disease, respectively. However, as we review here, recent advances have blurred this distinction.

On the one hand, the classical inflammatory diseases of the Brain also exhibit profound and early NeuroDegenerative features - remarkably, it has been known for more than a century that Neuronal damage is a key feature of Multiple Sclerosis pathology, yet this was neglected until very recently.

On the other hand, Immune mechanisms might set the pace of progressive CNS damage in primary NeuroDegeneration.

Despite differing initial events, increasing evidence indicates that even in clinically heterogeneous diseases, there might be common Immunological pathways that result in NeuroToxicity and reveal targets for more efficient therapies.

Purpose Of Review
Detailed ImmunoPathological assessment of Multiple Sclerosis tissue remains the research tool most likely to elucidate the major processes involved in disease pathogenesis and tissue injury.

Such studies steer and provide the impetus for refining cellular/molecular investigations and developing more relevant disease models in animals.

Recent Findings
Recent observations in early Multiple Sclerosis lesions challenge the traditional hypothesis that Multiple Sclerosis arises as the result of a primary Autoimmune process that specifically targets Myelin Antigen(s).

A new Multiple Sclerosis paradigm proposes that Oligodendrocyte Apoptosis is the earliest change in newly forming lesions.

And, that tissue injury is amplified by the subsequent recruitment of a systemic Immune Responses.

Over months to years the pathology of Multiple Sclerosis is transformed and the changes which accompany the late phase of the disease.

Suggest that the inflammatory response becomes progressively 'compartmentalized' and therefore largely isolated from systemic influence with time.

Summary
Recent pathological studies raise important questions regarding the etiology of Oligodendrocyte Apoptosis.

The mechanisms by which the accompanying inflammatory response amplifies tissue injury and the regulation of Central Nervous System immunity.

An improved understanding of these processes is essential for advancing therapeutic interventions applicable to different stages of the disease.

Multiple Sclerosis (MS) has traditionally been viewed and researched as an Immune-mediated disease with principal emphasis on the role of activated inflammatory cells, Oligodendrocytes and Astrocytes in its pathogenesis.

Abnormalities of Cerebral Endothelial Cells (CECs) is an under explored facet of MS pathogenesis and Vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease.

This review will focus on MS as a Central Nervous System (CNS) disease with a strong Vascular constituent and examines abnormalities within CECs in MS and their role in the loss of Blood-Brain Barrier and TransEndothelial migration of activated Leukocytes into the CNS.

One goal of this paper is to persuade and promote research on the Endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on Endothelial injury.

A deeper understanding of Endothelial pathophysiology in MS may help develop effective treatments through stabilization of Endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.

Background
The McDonald International Panel accepted the Barkhof/Tintore criteria for providing MRI evidence of dissemination in space to allow a diagnosis of Multiple Sclerosis in patients with Clinically Isolated Syndromes (CIS).

We applied these criteria in a large cohort of patients with CIS, representative of those seen in a general diagnostic setting, to assess their accuracy in predicting conversion to definite Multiple Sclerosis and to identify factors that affect this risk.

Methods
In a collaborative study of seven centres, baseline MRI and clinical follow-up data for 532 patients with CIS were studied, with the development of a second clinical event used as the main outcome.

All scans were scored for lesion counts and spatial lesion distribution to assess the fulfilment - ie, at least three out of four - of the Barkhof/Tintore criteria.

We used survival analysis and 2x2 tables to assess the test characteristics of the criteria at baseline.

Findings
Overall conversion rate was 32.5% with a median survival time of 85.3 months.

Fulfilment of the criteria at baseline showed, after a survival time of 2 years, a conversion rate of about 45% (95% CI 37-53) versus about 10% (6-16) in those with no asymptomatic lesions at baseline (p < 0.0001).

For patients with a follow-up of at least 2 years, the fulfilment of the MRI criteria showed an accuracy of 68% (sensitivity 49%, specificity 79%) for predicting conversion.

And an increase in risk of nearly four times for conversion compared with those not fulfilling the criteria (odds ratio 3.7, 95% CI 2.3-5.9; p < 0.0001).

Cox proportional hazards regression analysis accorded with this increased risk.

No effects were recorded on the performance of the criteria by sex, presenting symptoms, or center.

Age at baseline did have a small but significant effect as predictor (hazard ratio 0.97, 0.95-0.99; p = 0.002), but did not affect the prognostic value of the MRI criteria.

Interpretation
MRI abnormalities have important prognostic value.

The cut-off, based on the Barkhof/Tintore criteria, as incorporated in the McDonald diagnostic scheme yields acceptable specificity, but could have lower sensitivity than previously reported.

Background
Progression rates in Primary/Progressive Multiple Sclerosis (PPMS) vary widely and Brain Magnetization Transfer Imaging (MTI) has potential as an early prognostic indicator.

We investigated the predictive value of MTI and the longitudinal changes developing over one year in early PPMS.

Aims
To determine:

1. Whether baseline Brain MTI parameters in early PPMS predict clinical changes over one year
   • independently of Brain Volume
2. Whether change in MT parameters occurs over one year
   • independently of Atrophy

Methods
Thirty patients with PPMS within five years of symptom onset and 15 controls underwent MT and Volumetric imaging studies, at baseline and one year.

Patients underwent clinical assessment using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC), including the Timed Walk Subtest (TWT).

Normalized MT Histograms were generated for Whole Brain (WB), Normal-Appearing Brain Tissue (NABT), and Normal-Appearing White and Gray Matter (NAWM and NAGM) segments.

Multiple regression analyzes were performed to investigate whether baseline MTR parameters predicted clinical change over one year, adjusting for baseline Brain Volume. MTR changes over one year were assessed using paired t-tests.

Results
In patients lower baseline NAWM MTR predicted greater deterioration in EDSS and MSFC, particularly in walking ability measured by the TWT, independently of NAWM baseline volume (p=0.001).

NAGM MTR mean (p < 0.001), and to a lesser extent, NAWM mean (p=0.011) and lesion MTR (p=0.03) decreased over one year.

Conclusions
NAWM MTR may provide information on short-term clinical prognosis in early PPMS.

MTI is sensitive to Brain Tissue changes over one year in early PPMS, which were primarily seen in the NAGM

NeuroMyelitis Optica (NMO) is an Inflammatory DeMyelinating Disease that typically affects Optic Nerves and Spinal Cord. Its pathogenic relationship to Multiple Sclerosis (MS) is uncertain.

Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of Complement activation in a VasculoCentric pattern around thickened hyalinized blood vessels.

Suggesting a pathogenic role for Humoral Immunity targeting an Antigen in the PeriVascular Space.

A recently identified specific Serum AutoAntibody biomarker, NMO-IgG, targets Aquaporin-4 (AQP4).

The most abundant water channel protein in the CNS, which is highly concentrated in Astrocytic foot processes.

We analyzed and compared patterns of AQP4 ImmunoReactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with Infarcts and five normal controls.

In normal Brain, Optic Nerve and Spinal Cord, the distribution of AQP4 expression resembles the VasculoCentric pattern of Immune complex deposition observed in NMO lesions.

In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of DeMyelinating activity, extent of tissue Necrosis, or site of CNS involvement.

We identified a novel NMO lesion in the Spinal Cord and Medullary Tegmentum extending into the area postrema.

Characterized by AQP4 loss in foci that were Inflammatory and Edematous, but neither DeMyelinated nor Necrotic.

Foci of AQP4 loss coincided with sites of intense VasculoCentric Immune Complex deposition.

These findings strongly support a role for a Complement activating AQP4-specific AutoAntibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

See: Complement Abstract Index

Interferon-beta (IFN-ß) preparations are the most frequently prescribed therapies for patients with Relapsing Multiple Sclerosis (MS). Several open-label observational studies report similar efficacy among IFN-ß preparations.

The Quality Assessment in Multiple Sclerosis Therapy (QUASIMS) study is a large, open-label observational study designed to compare the effectiveness and tolerability of available IFN-ß preparations.

As disease-modifying therapies for Relapsing MS across a wide range of clinical practice settings.

This retrospective, controlled cohort study was conducted by chart review at 510 sites in Germany, Austria, and Switzerland.

Enrolled patients had received one of the four available IFN-ß preparations/dosing regimens (intramuscular IFN-ß-1a 30 microg 1x/week [Avonex((R))], subcutaneous (SC) IFN-ß-1a 22 or 44 microg 3x/week [Rebif((R))], or SC IFN-ß-1b 250 microg 3.5x/week [Betaferon/Betaseron((R))]) for >/= 2 years.

Preplanned outcomes at 1 and 2 years included change from baseline Expanded Disability Status Scale (EDSS) score, percentage of progression-free patients (< 1.0 EDSS point), annualized relapse rate (RR), percentage of relapse-free patients, and reasons for therapy change.

Of 4754 evaluable patients, 3991 (84%) received IFN-ß as initial therapy.

There were no significant differences among IFN-ßs when used as initial or follow-up therapy on almost all outcome variables.

Relapse rate was consistently higher and percentage of relapse-free patients consistently lower for all products used as follow-up versus initial therapy.

Results of QUASIMS showed similar effectiveness among IFN-ß products. Benefits were consistently superior when IFN-ß was used as initial rather than follow-up therapy.

Our results suggest that patients do not benefit in terms of disease outcome from switching between IFN-ß preparations/dosing regimens.

Brain Atrophy is a typical feature of many Neurological conditions. Therefore, quantitative evaluation and spatial characterization of Atrophy are potentially useful for monitoring the evolution of Central Nervous System (CNS) disorders.

In this study, a method for measuring Atrophy of the major White Matter (WM) fiber bundles in the Brain using Diffusion Tensor (DT) MRI data is developed.

To this end, an atlas was created from sets of Diffusion Anisotropy images from normal subjects, and the deformations necessary to match single subject Anisotropy images to this atlas were then computed.

Because Diffusion Anisotropy images were used, this approach should be sensitive to fiber bundle volume changes in the same way that using T₁-weighted images allows Gray Matter volume changes to be measured.

The Jacobian determinant of the deformation field for each subject was then used as a measure of contraction or expansion of the tissue at each image voxel.

An overview of the nonlinear registration problem is given; then an optimization of the parameters for the chosen algorithm is performed and the method for producing the atlas is described.

The effectiveness of the method was then tested on data from five patients with Multiple Sclerosis (MS) and two patients with Amyotrophic Lateral Sclerosis (ALS).

Magn Reson Med 58:527-534, 2007. (c) 2007 Wiley-Liss, Inc.

CXCL10 (Interferon-gamma-inducible protein-10) levels are increased in CerebroSpinal Fluid of Multiple Sclerosis (MS) patients with symptomatic attacks of Inflammatory DeMyelination, supporting a role for this molecule in MS pathogenesis.

Two hundred and twenty-six patients with MS and 235 controls were genotyped for G --> C and T --> C single nucleotide polymorphisms (SNPs) in exon 4 of CXCL10 gene.

Haplotypes were tested for association and correlated with clinical variables. The two SNPs studied were in complete linkage disequilibrium. None of the determined haplotypes was associated with MS.

However, carriers of the GGTT haplotype (defined as wild type, according to the sequence in National Centre for Biotechnology Information (NCBI) database) had a significantly lower progression index than non-carriers (P = 0.016).

Furthermore, amongst patients who had an initial Relapsing/Remitting (RR) course of the disease, the time between onset and second episode was significantly longer in GGTT carriers (P = 0.021).

Considering Secondary/Progressive (SP)-MS patients, the time between the initial RR form and the subsequent worsening to SP was longer in this group (P = 0.08).

Therefore, the GGTT haplotype of the CXCL10 gene is not a susceptibility factor for the development of MS, but is probably to influence the course of MS, possibly contributing to slow down the progression of the disease.

Background
AutoReactive AntiBodies (ARAB) occur more frequently in patients with Multiple Sclerosis (MS) than in general population and the presence of these AntiBodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS.

Methods
Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and Clinically Isolated Syndrome (CIS) patients were conducted.

The patients were evaluated for an extensive panel that included various subtypes of AntiPhosphoLipid AntiBody (APLA) including Anti-PhosphatidylEthanolamine (APE), Anti-PhosphatidylSerine (APS), Anti-ß-2-GlycoProtein-1 (ABGP), Anti-Cardiolipin (ACA), and several other ARAB such as AntiNuclear AntiBody (ANA), Anti-Neutrophilic Cytoplasmic AntiBodies (ANCA), Anti-Thyroid Peroxidase AntiBodies (ATA), anti-SS-A, and anti-SS-B AntiBodies.

Quantitative MRI analysis was performed in a subgroup of MS patients measuring T₂-lesion volume (LV), T₁ black hole LV and Brain Parenchymal Fraction (BPF).

Results
A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled.

Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS.

Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012).

The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent.

However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing.

In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T₂-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048).

The patients with ATA also had significantly higher T₂-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044).

Conclusions
ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T₂-LV.

Gray Matter hypointensity on T₂-weighted Magnetic Resonance Imaging (MRI) scans, suggesting Iron deposition, has been described in Multiple Sclerosis (MS) and is related to physical disability, disease course and Brain Atrophy.

We tested the hypothesis that SubCortical Gray Matter T₂ HypoIntensity is related to Cognitive Impairment after adjusting for the effect of MRI lesion and Atrophy measures. We studied 33 patients with MS and 14 healthy controls.

Normalized T₂ signal intensity in the Caudate, Putamen, Globus Pallidus and Thalamus, total Brain T₁-HypoIntense lesion volume (T₁LV), Fluid-Attenuated Inversion-Recovery-HyperIntense Lesion Volume (FLLV) and Brain Parenchymal Fraction (BPF) were obtained quantitatively.

A NeuroPsychological Composite Score (NCS) encompassed New Learning, Attention, Working Memory, Spatial Processing and Executive Function.

In each of the regions of interest, the normalized T₂ intensity was lower in the MS versus control group (all P < 0.001). Regression modelling tested the relative association between all MRI variables and NCS.

Globus Pallidus T₂ HypoIntensity was the only variable selected in the final model (R2 = 0.301, P = 0.007).

Pearson correlations between MRI and NCS were T₁LV: r = -0.319; FLLV: r = -0.347; BPF: r = 0.374; T₂ HypoIntensity of the Caudate: r = 0.305; Globus Pallidus: r = 0.395; Putamen: r = 0.321; and Thalamus: r = 0.265.

Basal Ganglia T₂ HypoIntensity and BPF demonstrated the strongest associations with Cognitive Impairment on individual Cognitive subtests.

SubCortical Gray Matter T₂ HypoIntensity is related to Cognitive Impairment in MS, supporting the clinical relevance of T₂ HypoIntensity as a biological marker of MS tissue damage.

These data implicate a role for Basal Ganglia Iron deposition in NeuroPsychological Dysfunction.

Approximately 5-25% of Interferon-beta (IFN-ß) treated Multiple Sclerosis (MS) patients develop anti-IFN-ß Neutralizing AntiBodies (NAb) but the patient-specific variables associated with the risk of developing Anti-IFN-ß AntiBodies are poorly understood.

Anti-IFN-ß NAb are a subset of anti-IFN-ß binding AntiBodies (BAb) and all patients with NAb generally have high levels of associated BAb.

The purpose of this research was to assess the association between AutoReactive AntiBodies (ARAB) and the risk of developing Anti-IFN-ß BAb in MS patients.

This was a retrospective study that included consecutive patients diagnosed with clinically definite MS evaluated at our center and considered appropriate for IFN-ß therapy.

The patients were tested for various subtypes of AntiPhosphoLipid AntiBodies (APLA) including Anti-PhosphatidylEthanolamine (APE), Anti-PhosphatidylSerine (APS), and Anti-Cardiolipin (ACA) AntiBodies, and other ARAB, AntiNuclear and Anti-Neutrophilic Cytoplasmic AntiBodies, Anti-Thyroid Peroxidase AntiBodies (ATA), anti-SS-A and anti-SS-B AntiBodies.

BAb levels were assessed using a commercial binding ELISA assay. A total of 33 patients (mean age: 45.4 years, 85% female) were enrolled; 15 patients were negative and 18 patients were positive for BAb.

APLA or ATA were present in 95% (17 of 18 patients) of patients positive for BAb.

In comparison, APLA or ATA occurred in only 27% (four of 15 patients) of patients in the BAb negative group.

The associations between the occurrence of BAb and the occurrence of high APLA or ATA were significant (chi(2)=13.4, P < 0.001 in Fisher exact test).

The odds ratio for the association was 46.8 (with a 95% confidence interval range of 4.6-475). No significant correlations were found for other ARAB.

The presence of AutoReactive AntiBodies, particularly APLA and ATA is associated with increased risk of occurrence of IFN-ß BAb in MS patients on long-term IFN-ß therapy.

Multiple Sclerosis 2007; 00: 000-000. http://msj.sagepub.com.